The multiple physiological, pathological and immunological activities of bacterial endotoxins (lipopolysaccharides, LPS) have been well documented. A primary reason for this broad spectrum of activities is the almost ubiquitous capacity of these potent bacterial products to interact with host defense systems. There is now abundant evidence which indicates that the lipid A region of the LPS macromolecule is critical for the expression of biological activity of endotoxin. However, the complexity of the subunit structures which comprise the LPS maacromolecule has only recently been fully appreciated. Recent evidence from this laboratory has provided evidence for a dominant role for lipid A rich (R-LPS) subunits in mediating the effects of LPS and experiments are proposed to test the validity of this hypothesis by the preparation of LPS macromolecules with highly defined subunit composition. Studies are also proposed to examine the biochemical basis for the postulated requirement for R-LPS subunits as assessed by their interaction with mammalian cell membranes. We and others have postulated that non-specific hydrophobic interactions of LPS (lipid A) with cell membranes contributes to the activation of lymphoid cells and macrophages by LPS. Some recent experiments from this laboratory have demonstrated selective association of R-LPS subunits with lymphocytes. Finally, it is proposed to define an evaluate both biochemically and biologically the LPS macromolecules released from bacteria following their interaction with host defense systems, particularly the serum complement system and the phagocytic macrophage. Our experiments to date have suggested that, in both of these systems a selective release of LPS subunits is effected by these host defense systems which may well dictate their expression of biological activity. These collective experiments to define the interaction of bacterial endotoxins with host mediation systems will provide fundamental information on the contribution of these biologically active macromolecules to the hypotension and disseminated intravascular coagulation characteristic of patients with gram negative sepsis.